Since its description by Dole1 in the 1960's and demonstration by Fenn2, 3 in 1984, electrospray ionization (ESI) has become the standard in the analysis of biomolecules, especially proteins and peptides. Generally, ESI is achieved by spraying a solution of analyte through a needle (called the emitter), across a potential difference. The resulting charged droplets undergo a series of fissions to form gaseous phase ions, which can be separated and detected by mass spectrometry (MS). The appeal of ESI for use with biomolecules is especially due to its ability to ionize large molecules without their destruction, unlike other ionization techniques such as electron impact.4 The concomitant development in various mass spectrometer platforms (e.g., FT-ICR, QqQ, QTOF, etc.) that can be interfaced to ESI has also largely contributed to the development of the field in general.
An improvement over conventional ESI (flow rates>1 μL/min) has been the development of low flow ESI (flow rates<100 nL/min), also known as nanoelectrospray, described by Wilm and Mann in 1996.9 The impetus for taking electrospray to nano levels has been largely due to the characteristic advantages born from formation of smaller droplets (reported to be approximately 180 nm). Such droplets have higher surface area to volume ratios than that of conventional ESI so that they can be easily desolvated, resulting in enhanced sensitivity. Furthermore, nanoelectrospray provides improved efficiency of ionization and ion transmission, resulting in low-level detection limits and an extended dynamic range, which is important in fields such as quantitative clinical proteomics and other areas of biomolecule analysis such as metabolomics and glycomics. The low flow rate used means one gets better sample economy (<5 μL), and moreover the improved desolvation at such low flow rates alleviates the need for a nebulizing gas. Nanoelectrospray has also been found to minimize greatly (and to eliminate at low nano flow rates (<50 nL/min)) ion suppression and matrix effects which can seriously plague regular ESI.9-16 
Essential to the performance of nanoESI is a minimized sample stream for electrospray to the mass spectrometer. The interest in emitter development is mainly because of the pivotal role that emitters play in ensuring the success of nanoelectrospray. Indeed, the sensitivity, stability and reproducibility of nanoelectrospray are all highly dependent on the emitter characteristics. Wilm et al.9 employed a pulled-glass substrate as an emitter, and demonstrated its improved electrospray performance at nano level flow rates. The format of such a tapered fused silica capillary with aperture<20 μm has been widely accepted as a commercial nano-emitter tip. However, such pulled-tip emitters have serious limitations, including their susceptibility to clogging due to the internal tapering and constricted aperture, limited range of possible flow rates, and poor reproducibility, impeding quantitation in fields such as proteomics.
To address such limitations associated with single aperture tapered emitters, interest has developed in multi-flowpath emitters. The use of multi-channel tips has been found to improve sensitivity significantly (sensitivity is proportional to the square root of the number of produced Taylor cones) and to extend the lifespan of emitter tips by reducing clogging. To develop multi-channel emitters, several groups including Smith17, 18 and Wang19 have borrowed techniques such as Micro Electro Mechanical Systems (MEMS), commonly employed in the electronics industry and recently used in the microfluidic chips industry, for emitter fabrication.20-22 One of the emitters fabricated using MEMS technology has been branded the Microfabricated Monolithic Multinozzle emitter (M3), which has attracted considerable interest within the proteomics industry.19 Although promising due to its high reproducibility, throughput, and amenability for automation, this technique requires expensive equipment and clean room facilities, which results in a very expensive emitter.
Kelly et al.17, 18 have reported a linear array of HF etched open tubular silica emitters. The linear array, which was made from multiple silica capillaries and required a custom made multi-capillary MS inlet, provided a significant increase in sensitivity and ion transmission efficiency. We have demonstrated improved ESI efficiency by employing emitters with a porous polymer monolith for nanoelectrospray.23,24 As a progression from this, we recently developed a highly robust emitter by entrapping ODS spheres using a porous polymer network, creating an emitter with numerous pores, each behaving like an emitter, which radically reduces chances of clogging25 (see also International Patent Application Publication No. WO 2006/092043). Nevertheless, none of these emitters offers the combination of ease of production and low cost, while meeting stringent performance requirements.